Our laboratory investigations are focused on identifying genes that regulate the growth, differentiation, and programmed cell death of normal and malignant mammary epithelial cells. Our ultimate goal is to gain understanding into the molecular pathways that control the fate of mammary cells in order to develop rational strategies for the treatment of breast cancer. Currently, we have three projects investigating genes that are involved in pathways of growth, differentiation, and apoptosis. 1) We have cloned and begun to characterize cbl-b, a new SH3 binding protein with homology to the c-cbl proto-oncogene. Cbl-b and c-cbl are novel signal transduction molecules downstream of receptor tyrosine kinases. Ongoing work is focused on elucidating the role that these genes play in the growth stimulation mediated by the EGF family of receptor tyrosine kinases in mammary epithelial cells. 2) We have identified several protein tyrosine phosphatases which are expressed in breast cancer cells and are beginning to characterize their function. Expression of one of these protein tyrosine phosphatases (DEP-1) is increased when breast cancer cells are induced to differentiate in vitro. DEP-1 is a membrane receptor phosphatase and over-expression of the protein inhibits the growth of breast cancer cells in culture. Further studies are underway to investigate the biochemical pathways affected by this receptor phosphatase. 3) We have demonstrated that the Fas/APO- 1 protein, a membrane receptor capable of triggering apoptosis upon ligand binding, is expressed at high levels on normal mammary epithelial cells in culture but only a low levels in breast cancer cell lines. Additional experiments have shown that the receptor can induce apoptosis in the normal mammary epithelial cells. Current work is focused on increasing the expression of Fas/APO-1 on breast cancer cells in order to induce cell death.